Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53‐ALOX15 signaling pathway

Abstract

Background Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non‐apoptotic type of cell death that has only recently been identified, which is marked primarily by iron‐dependent and lipid‐derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous. Methods In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin‐induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro. Results First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis‐related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53. Conclusions Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.

Ferroptosis and mitochondrial dysfunction in acute central nervous system injury

“…Following injury, the SCI group displayed increased levels of STAT3 , JUN , TLR4 , ATF3 , HMOX1 , PTGS2 , and RELA mRNA, while VEGFA , MAPK1 , and MAPK9 mRNA levels were found to be decreased, as confirmed by real-time PCR analysis, in comparison to the sham group, 1 day post-injury. This pattern was not observed in the sham group ( Li et al, 2023 ). DHODH expression and enzymatic activity have been implicated in cancer progression in previous studies.…”

SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3

“…ATF3 is proven by accumulating evidences to play dual roles in regulating the occurrence of ferroptosis. Different with transcription factor p53 whose activation leads to ferroptosis in both cancer cells and non-cancerous cells [ 32 , 33 ], ATF3 inhibits ferroptosis in non-cancerous cells but promotes cancer cell ferroptosis. It was reported that ATF3 activation obviously attenuated cardiomyocyte ferroptosis provoked by erastin or RSL3, as well as suppressed neuron ferroptosis triggered by ischemic stroke [ 34 , 35 ].…”

Molecular mechanisms of ferroptosis and its antitumor applications in natural products

“…For example, GPX4 inhibits TMEM16A-mediated hepatic ischemia/reperfusion injury [159] . Additionally, DHODH inhibits ferroptosis in spinal cord injury [51] ; similarly, ferroptosis exacerbates most cardiovascular diseases [160] . Notably, trastuzumab induces severe cardiotoxicity while treating breast cancer via ferroptotic cell death; however, SGLT2 inhibitors eliminate cardiotoxicity and show potent antitumor activity [161] .…”

“…Ferroptosis suppressor protein 1 (FSP1) uses NAD(P)H to reduce CoQ10 to CoQH2, thereby scavenging lipid peroxidation radicals [ 48 , 49 ]. Unlike FSP1, although dihydrogen phosphate dehydrogenase (DHODH) also neutralizes lipid peroxidation by increasing CoQH2 synthesis, this process occurs mainly in mitochondria, so GPX4 and DHODH can collaborate to enhance the inhibition of mitochondrial lipid peroxidation, but cytoplasmic GPX4 and FSP1 cannot [ 50 , 51 ]. Similarly, GTP cyclohydrolase 1 (GCH1) acts as a radical-trapping antioxidant by generating BH4 to inhibit ferroptosis [ 52 – 54 ].…”